Exon skipping induces uniform dystrophin rescue with dose-dependent restoration of serum miRNA biomarkers and muscle biophysical properties
<p>Therapies that restore dystrophin expression are presumed to correct Duchenne muscular dystrophy (DMD), with antisense-mediated exon skipping being the leading approach. Here we aimed to determine whether exon skipping using a peptide-phosphorodiamidate morpholino oligonucleotide (PPMO) con...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Cell Press
2022
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| _version_ | 1797111335496974336 |
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| author | Chwalenia, K Oieni, J Zemła, J Lekka, M Ahlskog, N Coenen-Stass, AML McClorey, G Wood, MJA Lomonosova, Y Roberts, TC |
| author_facet | Chwalenia, K Oieni, J Zemła, J Lekka, M Ahlskog, N Coenen-Stass, AML McClorey, G Wood, MJA Lomonosova, Y Roberts, TC |
| author_sort | Chwalenia, K |
| collection | OXFORD |
| description | <p>Therapies that restore dystrophin expression are presumed to correct Duchenne muscular dystrophy (DMD), with antisense-mediated exon skipping being the leading approach. Here we aimed to determine whether exon skipping using a peptide-phosphorodiamidate morpholino oligonucleotide (PPMO) conjugate results in dose-dependent restoration of uniform dystrophin localization, together with correction of putative DMD serum and muscle biomarkers. Dystrophin-deficient <em>mdx</em> mice were treated with a PPMO (Pip9b2-PMO) designed to induce <em>Dmd</em> exon 23 skipping at single, ascending intravenous doses (3, 6, or 12 mg/kg) and sacrificed 2 weeks later. Dose-dependent exon skipping and dystrophin protein restoration were observed, with dystrophin uniformly distributed at the sarcolemma of corrected myofibers at all doses. Serum microRNA biomarkers (i.e., miR-1a-3p, miR-133a-3p, miR-206-3p, miR-483-3p) and creatinine kinase levels were restored toward wild-type levels after treatment in a dose-dependent manner. All biomarkers were strongly anti-correlated with both exon skipping level and dystrophin expression. Dystrophin rescue was also strongly positively correlated with muscle stiffness (i.e., Young’s modulus) as determined by atomic force microscopy (AFM) nanoindentation assay. These data demonstrate that PPMO-mediated exon skipping generates myofibers with uniform dystrophin expression and that both serum microRNA biomarkers and muscle AFM have potential utility as pharmacodynamic biomarkers of dystrophin restoration therapy in DMD.</p> |
| first_indexed | 2024-03-07T08:07:20Z |
| format | Journal article |
| id | oxford-uuid:ef05285d-bc6a-4f34-9683-5b01ad5d9b37 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:07:20Z |
| publishDate | 2022 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:ef05285d-bc6a-4f34-9683-5b01ad5d9b372023-11-08T09:33:25ZExon skipping induces uniform dystrophin rescue with dose-dependent restoration of serum miRNA biomarkers and muscle biophysical propertiesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ef05285d-bc6a-4f34-9683-5b01ad5d9b37EnglishSymplectic ElementsCell Press2022Chwalenia, KOieni, JZemła, JLekka, MAhlskog, NCoenen-Stass, AMLMcClorey, GWood, MJALomonosova, YRoberts, TC<p>Therapies that restore dystrophin expression are presumed to correct Duchenne muscular dystrophy (DMD), with antisense-mediated exon skipping being the leading approach. Here we aimed to determine whether exon skipping using a peptide-phosphorodiamidate morpholino oligonucleotide (PPMO) conjugate results in dose-dependent restoration of uniform dystrophin localization, together with correction of putative DMD serum and muscle biomarkers. Dystrophin-deficient <em>mdx</em> mice were treated with a PPMO (Pip9b2-PMO) designed to induce <em>Dmd</em> exon 23 skipping at single, ascending intravenous doses (3, 6, or 12 mg/kg) and sacrificed 2 weeks later. Dose-dependent exon skipping and dystrophin protein restoration were observed, with dystrophin uniformly distributed at the sarcolemma of corrected myofibers at all doses. Serum microRNA biomarkers (i.e., miR-1a-3p, miR-133a-3p, miR-206-3p, miR-483-3p) and creatinine kinase levels were restored toward wild-type levels after treatment in a dose-dependent manner. All biomarkers were strongly anti-correlated with both exon skipping level and dystrophin expression. Dystrophin rescue was also strongly positively correlated with muscle stiffness (i.e., Young’s modulus) as determined by atomic force microscopy (AFM) nanoindentation assay. These data demonstrate that PPMO-mediated exon skipping generates myofibers with uniform dystrophin expression and that both serum microRNA biomarkers and muscle AFM have potential utility as pharmacodynamic biomarkers of dystrophin restoration therapy in DMD.</p> |
| spellingShingle | Chwalenia, K Oieni, J Zemła, J Lekka, M Ahlskog, N Coenen-Stass, AML McClorey, G Wood, MJA Lomonosova, Y Roberts, TC Exon skipping induces uniform dystrophin rescue with dose-dependent restoration of serum miRNA biomarkers and muscle biophysical properties |
| title | Exon skipping induces uniform dystrophin rescue with dose-dependent restoration of serum miRNA biomarkers and muscle biophysical properties |
| title_full | Exon skipping induces uniform dystrophin rescue with dose-dependent restoration of serum miRNA biomarkers and muscle biophysical properties |
| title_fullStr | Exon skipping induces uniform dystrophin rescue with dose-dependent restoration of serum miRNA biomarkers and muscle biophysical properties |
| title_full_unstemmed | Exon skipping induces uniform dystrophin rescue with dose-dependent restoration of serum miRNA biomarkers and muscle biophysical properties |
| title_short | Exon skipping induces uniform dystrophin rescue with dose-dependent restoration of serum miRNA biomarkers and muscle biophysical properties |
| title_sort | exon skipping induces uniform dystrophin rescue with dose dependent restoration of serum mirna biomarkers and muscle biophysical properties |
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